Post-Exposure Rabies Regimens for

Immunodeficiency Patients

Suda Punrin, MD.

Immunodeficiency

• Primary

• Secondary

Chinen J, Shearer WT. J Allergy Clin Immunol 2010;125:S195-203

Secondary (acquired) immunodeficiency

Rabies vaccination

• HIV infection

• Malignancy

• Transplantation

• Immunosuppressive drugs

Rabies vaccination

• HIV infection

• Malignancy

• Transplantation

• Immunosuppressive drugs

Deshpande, 1999 ESSEN IM

57% of symptomatic HIV-infected pts had

Nab 0.5

Jaijareonsup, 1999 TRC-ID + ERIG

4/9 of HIV-infected pts (CD4+ 316-950)

had Nab 0.5

Thisayakorn, 2000 IM PrEP in HIV-

infected children CD4+ < 15% had

lower Nab

Tantawichien, 2001 Double TRC-ID +

HRIG HIV-infected pts

(CD4+ 25 – 199)had Nab < 0.5

Tantawichien, 2009

Double ESSEN+adjuvant HIV-infected pts CD4+ < 100 had

Nab < 0.5

Sirikwin, 2009

Modified 8-sites ID HIV-infected pts CD4+ 69-190 on

HAART All had Nab 0.5

Gelinck, 2009 IM Day 0,84

HIV-infected pts CD4+ 353 -772

All had Nab 0.5

Azzoni, 2012

IM Day 0,7,42,378 HIV-infected pts

on regular HAART had Nab 0.5

Clinical trials

1999 2000 2009 2012

HIV & Rabies vaccination

Nab; neutralizing antibody

Regimens Nab < 0.5 IU/mL Nab ≥ 0.5 IU/mL

5-dose IM (ESSEN)

- 43% symptomatic (CD4+ < 400) - 24% asymptomatic CD4+ ? Anti-retroviral therapy (ARV) ?

TRC-ID (2-2-2-0-1-1) + ERIG

55 % of CD4+ < 300

CD4+ > 300

Double doses TRC-ID (4-4-4-0-2-2) + HRIG

43% of CD4+ < 200

CD4+ > 200 All on ARV

Double doses ESSEN-IM (2-2-2-2-2) + Aluminium adjuvanted TT

5/7 (71 %) of CD4+ < 100 (4/7 patient on ARV)

CD4+ > 250 2/7 (29%) of CD4+ > 100 (One patient on ARV)

Modified 8-site ID (8-8-8-8-8)

81% on ARV 66% had CD4+ > 200 One had CD4+ 69

HIV on ARV

Thai &WHO-approved regimens

Double doses (x2)

Modified 8-site ID

Double doses ESSEN +

aluminium adjuvanted

CD4+ > 300

CD4+ 200-300

CD4+ 100-200

NA

CD4+ < 100

?

โดนกัดมาอีกแล้ว !

Booster Re-start

Abbas AK et al. Cellular and Molecular immunology. Eighth Edition

0

5

10

15

20

25

30

35

D0 D7 D14 D28 D90 D180 D360

HIV Booster IM day 0,3

0.5

Nab ≥ 0.5 IU/mL since day 7 - 360 97% on HAART

Median CD4+ = 489

(range 94 – 1120)

GMT (IU/mL)

Punrin S, et. al. Proceedings of the 22th ECCMID. 31 March - 3 April 2012, London, United Kingdom.

Remarks

• One AIDS participants, who was vaccinated since seronegativity, had anamnestic response to booster injection

• One patients who had CD4+ count < 100, somehow, had the remaining seroprotective titers from the prior immunization

Remarks

• An AIDS patient who antecedently failed to seroconvert after PEP could evoke the immunologic memory response after quantitative CD4+ count recovery by HAART

Cell-mediated immune responses to intradermal rabies vaccination

Phanuphak P et al. Asian Pacific Journal of Allergy and Immunology 1987;5:33-7 Ratanavongsiri J, et. al. Asian Pac J Allergy Immunol 1985;3:187-90

Intradermal Intramuscular

0

5

10

15

20

25

30

35

D 0 D 7 D 14

Gr 1: 4 site-ID

Gr 2: IM Day 0,3

GMT (IU/mL)

Esp, CD4+ ≥ 500 (p=0.03)

100 % on HAART, median CD4+ = 622, HIV RNA < 20 copies/mL

Serrano-Villar S, et. al. Lancet HIV 2015;2:76-7 Lu W, et. al. J Int AIDS Soc 2015;18:20052

CD4/CD8 ratio: a re-emerging biomarker for HIV

A low ratio is associated with T cell activation, senescence, dysfunction and chronic inflammation

CD8+

CD4+

CD4+/CD8+ ratio & Nab day 7

Being primary rabies immunized during AIDS conditions had affected subsequent booster vaccination despite quantitative CD4+ T-cell recovery

Remarks

• Concept of pre-immunization of HIV-infected persons before the immunosuppression progressed might be considerably applicable to those at greatest risk

Longevity of Nab in HIV

• Four years interval from the latest immunization, 86.8% of patients had Nab > 0.5 IU/ml

• One volunteer had found endurance of seroconversion for 15 years

• However, a few patients who recently got rabies vaccine within one year could not maintain acceptable seroprotective level

Selected cases of HIV patients might receive rabies booster vaccination if…

• Asymptomatic, on HAART, CD4+ > 200

• No opportunistic infections

• No severe chronic medical conditions

• No other immunosuppressive conditions

• Received complete post-exposure rabies prophylaxis with cell-cultured vaccine within 10 years

Suggestion for rabies booster vaccination

• Only single visit 4-site ID and conventional IM day 0 and 3 regimens could be used

• Booster with full schedule regimens for every exposure

• Wound treatment is still the mandatory

Safety of rabies vaccination in HIV-infected patients

• Inactivated vaccine

• No serious adverse reactions

• No long term effect to CD4+ and HIV RNA level

• No effect to HIV progression

WHO Expert Consultation on Rabies. Second report. 2013;1-139

WHO recommendation

• Wound treatment

• Local infiltration of RIG

• Five IM doses of rabies vaccine

(asymptomatic, on HAART, recent CD4+ > 300)*

• Check rabies neutralizing antibody

• Observe responsible cat or dog for 10 days*

• When in doubt, consult specialist

* Suda’s opinions

Rabies vaccination

• HIV infection

• Malignancy

• Transplantation

• Immunosuppressive drugs

Hay E, et. al. JAMA 2001;285:166-7 Rahimi P, et. al. PLoS One 2015;10:e0139171

Kopel E, et. al. Emerg Infect Dis 2012;18:1493-5 Wiwanitkit V. Iran J Cancer Prev 2014;7:105-6

Malignancy Regimens

Lymphoma (4) ESSEN IM + HRIG ± Double doses ESSEN + HRIG

Acute myeloid leukemia (1) Double dose IM day 0 2-1-1-1-1 (no Nab)

Malignancy (non-specific) (5) ESSEN IM

CA Breast stage IV (Brain & bone metastasis)

On radiation & received corticosteroids

I ESSEN IM + HRIG II Booster IM Day 0,3

Nab (IU/ml)

D 0 = negative

D 7 = 0.53

D 14 = 0.28 **

D 28 = 0.28 **

D 60 = > 0.5

D 74 = > 0.5

D 120 = > 0.5

Stop radiation, Prednisolone 10 mg/day

Suda Punrin, et. al. Proceedings of 23th ECCMID, 27 - 30 April 2013, Berlin, Germany

Non-Hodgkin lymphoma stage IV, in remission

- Completed R-CHOP course 3 mo ago

- Received PEP x2 times before diagnosis of NHLs

I Booster IM Day 0,3 II Booster IM Day 0,3

Nab (IU/ml) D 0 = 2.41 D 14 = 2.52 D 90 = 2.73 D 104 = 3.22

Recurrence of NHLs in the next 4 months

Suda Punrin, et. al. Proceedings of 23th ECCMID, 27 - 30 April 2013, Berlin, Germany

Severity

Stage Treatment

Immune status

Rabies vaccination

• HIV infection

• Malignancy

• Transplantation

• Immunosuppressive drugs

Rubin LG. et. al. Clin Infect Dis 2013:1-57 Eibl M., Wolf H. Immunotherapy 2015;7:1273–92

Vora M. et. al. Transpl Infect Dis 2015;17:389–95

ESSEN IM (1-1-1-1-1) + RIG

Rabies vaccination

• HIV infection

• Malignancy

• Transplantation

• Immunosuppressive drugs

Rubin LG. et. al. Clin Infect Dis 2013:1-57 Eibl M., Wolf H. Immunotherapy 2015;7:1273–92

อรพิน เลิศวรรณวิทย์ วิทยานิพนธ์ปริญญามหาบัณฑิต ภาควิชาอายุรศาสตร์ คณะแพทยศาสตร์ จุฬาลงกรณ์มหาวิทยาลัย 2555

การตอบสนองทางภูมิคุ้มกันต่อการได้รับวัคซีนป้องกันโรคพิษสุนัขบ้า ในอาสาสมัครที่ได้รับยาสเตียรอยด ์

Modified TRC-ID (2-2-2-0-2) On prednisolone ≥ 20 mg/day at least 3 weeks or

accumulative dose ≥ 700 mg & receiving 10 mg/day Autoimmune hemolytic anemia, nephrotic syndrome, hypereosinophilia, Pemphigus vulgaris, Pemphigus foliaceus, Alopecia areata, ITP, COPD, Lupus profundus, Evan syndrome and bullous LE, SLE, rheumatoid arthritis

81.3% of pateints had Nab > 0.5 IU/mL โรคประจ าตัวในกลุ่มโรคผิวหนัง และ ระยะเวลาในการรับประทานยาสเตียรอยด์ที่มากกว่า 1 ปี สัมพันธ์กับระดับ Nab ที่น้อยกว่า 0.5 IU/mL

U.S. ACIP recommendation

• Immunosuppressive agents should not be administered during PEP

• Nab should be checked to ensure that acceptable antibody response has developed

Manning SE, et al. MMWR Recomm Rep 2008;57:1-28

WHO Expert Consultation on Rabies. Second report. 2013;1-139

WHO recommendation

• Wound treatment

• Local infiltration of RIG

• Five IM doses of rabies vaccine

• Check rabies neutralizing antibody

• When in doubt, consult specialist

Acknowledgements

Thank you for your attention